C-Abl inhibition; a novel therapeutic target for Parkinson’s disease

Parkinson’s disease (PD) is the most prevalent movement disorder in the world. The major pathological hallmarks of PD are death of dopaminergic neurons and the formation of Lewy bodies. At the moment, there is no cure for PD; current treatments are symptomatic. Investigators are searching for neuroprotective agents and disease modifying strategies to slow the progress of PD. However, recently, due to the ignorance of the main pathological sequence of PD, many drug targets failed to provide neuroprotective effects in human trials. Currently, a huge amount of evidence suggests the involvement of C-Abelson (c-Abl) tyrosine kinase enzyme in the pathology of PD. C-abl plays a role in PD pathology on the levels of parkin activation, alpha synuclein aggregation, and impaired autophagy of toxic elements. Experimental studies showed that (1) c-abl activation is involved in neuronal death and (2) c-abl inhibition shows neuroprotective effects and prevents dopaminergic neurons’ death. Current evidence from experimental studies and the first in-human trial shows that c-abl inhibition holds the promise for neuroprotection against PD and therefore, justifies the movement towards larger clinical trials. In this review article, we discussed the role of c-abl in PD pathology and the findings of preclinical experiments and the first in-human trial. In addition, based on the lessons of the last decade and current preclinical evidence, we provide recommendations for future research in this area

Laparoscopy in management of appendicitis in high-, middle-, and low-income countries: a multicenter, prospective, cohort study.

BACKGROUND: Appendicitis is the most common abdominal surgical emergency worldwide. Differences between high- and low-income settings in the availability of laparoscopic appendectomy, alternative management choices, and outcomes are poorly described. The aim was to identify variation in surgical management and outcomes of appendicitis within low-, middle-, and high-Human Development Index (HDI) countries worldwide. METHODS: This is a multicenter, international prospective cohort study. Consecutive sampling of patients undergoing emergency appendectomy over 6 months was conducted. Follow-up lasted 30 days. RESULTS: 4546 patients from 52 countries underwent appendectomy (2499 high-, 1540 middle-, and 507 low-HDI groups). Surgical site infection (SSI) rates were higher in low-HDI (OR 2.57, 95% CI 1.33-4.99, p = 0.005) but not middle-HDI countries (OR 1.38, 95% CI 0.76-2.52, p = 0.291), compared with high-HDI countries after adjustment. A laparoscopic approach was common in high-HDI countries (1693/2499, 67.7%), but infrequent in low-HDI (41/507, 8.1%) and middle-HDI (132/1540, 8.6%) groups. After accounting for case-mix, laparoscopy was still associated with fewer overall complications (OR 0.55, 95% CI 0.42-0.71, p < 0.001) and SSIs (OR 0.22, 95% CI 0.14-0.33, p < 0.001). In propensity-score matched groups within low-/middle-HDI countries, laparoscopy was still associated with fewer overall complications (OR 0.23 95% CI 0.11-0.44) and SSI (OR 0.21 95% CI 0.09-0.45). CONCLUSION: A laparoscopic approach is associated with better outcomes and availability appears to differ by country HDI. Despite the profound clinical, operational, and financial barriers to its widespread introduction, laparoscopy could significantly improve outcomes for patients in low-resource environments. TRIAL REGISTRATION: NCT02179112

Titanium elastic nails versus spica cast in pediatric femoral shaft fractures:A systematic review and meta-analysis of 1012 patients

Background: There is a general consensus on the management of femoral fractures in children younger than two years and adolescents older than sixteen years. The best treatment for patients younger than sixteen years of age is still debatable. Titanium Elastic Nails (TEN), is widely used with some evidence, nonetheless, we undertook a systematic meta-analysis to assess the efficacy of TEN compared to Spica cast for the management of femoral shaft fracture in children aged between 2 to 16 years old. Methods: A computer literature search of PubMed, Scopus, Web of Science, CINAHL and Cochrane Central was conducted using relevant keywords. We included clinical trials and observational studies that compared TEN versus Spica cast; Records were screened for eligible studies and data were extracted and synthesized using Review Manager version 5.3 for Windows. Our search found 573 unique articles. After screening the abstract and relevant full text, 12 studies with a total of 1012 patients were suitable for the final analysis. Results: In terms terms of union (in weeks), the reported effect sizes favoured the TEN group in two included studies only. Moreover, the overall standardized mean difference in sagittal (SMD -0.48, 95% CI [-0.70 to -0.26], P<0.001) and coronal angulations (SMD -0.66, 95% CI [-1.00 to -0.31], P<0.001) favored TEN fixation in management of femoral fractures younger than 16 years. The reported length of hospital stay was not consistent across studies. The overall risk ratio of malalignment (RR=0.39, 95% CI [0.27 to 0.57], P<0.001) favored the TEN as well as walking independently. Based on our analysis, TEN treatment is superior to traction and hip spica for femoral fractures in patients younger than 16 years old. Conclusion: Based on our analysis we recommend the use of TEN fixation in management of pediatric femoral fractures in patients younger than 16 years

Prevalence of spine surgery navigation techniques and availability in Africa: A cross-sectional study

Background: Africa has a large burden of spine pathology but has limited and insufficient infrastructure to manage these spine disorders. Therefore, we conducted this e-survey to assess the prevalence and identify the determinants of the availability of spine surgery navigation techniques in Africa. Materials and methods: A two-part questionnaire was disseminated amongst African neurological and orthopedic surgery consultants and trainees from January 24 to February 23, 2021. The Chi-Square, Fisher Exact, and Kruskal-Wallis tests were used to evaluate bivariable relationships, and a p-value \u3c0.05 was considered statistically significant. Results: We had 113 respondents from all regions of Africa. Most (86.7 %) participants who practiced or trained in public centers and centers had an annual median spine case surgery volume of 200 (IQR = 190) interventions. Fluoroscopy was the most prevalent spine surgery navigation technique (96.5 %), followed by freehand (55.8 %), stereotactic without intraoperative CT scan (31.9 %), robotic with intraoperative CT scan (29.2 %), stereotactic with intraoperative CT scan (8.8 %), and robotic without intraoperative CT scan (6.2 %). Cost of equipment (94.7 %), lack of trained staff to service (63.7 %), or run the equipment (60.2 %) were the most common barriers to the availability of spine instrumentation navigation. In addition, there were significant regional differences in access to trained staff to run and service the equipment (P = 0.001). Conclusion: There is a need to increase access to more advanced navigation techniques, and we identified the determinants of availability

Prevalence of spine surgery navigation techniques and availability in Africa: A cross-sectional study

Background: Africa has a large burden of spine pathology but has limited and insufficient infrastructure to manage these spine disorders. Therefore, we conducted this e-survey to assess the prevalence and identify the determinants of the availability of spine surgery navigation techniques in Africa. Materials and methods: A two-part questionnaire was disseminated amongst African neurological and orthopedic surgery consultants and trainees from January 24 to February 23, 2021. The Chi-Square, Fisher Exact, and Kruskal-Wallis tests were used to evaluate bivariable relationships, and a p-value \u3c0.05 was considered statistically significant. Results: We had 113 respondents from all regions of Africa. Most (86.7 %) participants who practiced or trained in public centers and centers had an annual median spine case surgery volume of 200 (IQR = 190) interventions. Fluoroscopy was the most prevalent spine surgery navigation technique (96.5 %), followed by freehand (55.8 %), stereotactic without intraoperative CT scan (31.9 %), robotic with intraoperative CT scan (29.2 %), stereotactic with intraoperative CT scan (8.8 %), and robotic without intraoperative CT scan (6.2 %). Cost of equipment (94.7 %), lack of trained staff to service (63.7 %), or run the equipment (60.2 %) were the most common barriers to the availability of spine instrumentation navigation. In addition, there were significant regional differences in access to trained staff to run and service the equipment (P = 0.001). Conclusion: There is a need to increase access to more advanced navigation techniques, and we identified the determinants of availability

Chloroquine and hydroxychloroquine for the prevention and treatment of COVID-19: A fiction, hope or hype? An updated review

In December 2019, the novel coronavirus disease pandemic (COVID-19) that began in China had infected so far more than 109,217,366 million individuals worldwide and accounted for more than 2,413,912 fatalities. With the dawn of this novel coronavirus (SARS-CoV-2), there was a requirement to select potential therapies that might effectively kill the virus, accelerate the recovery, or decrease the case fatality rate. Besides the currently available antiviral medications for human immunodeficiency virus (HIV) and hepatitis C virus (HCV), the chloroquine/hydroxychloroquine (CQ/HCQ) regimen with or without azithromycin has been repurposed in China and was recommended by the National Health Commission, China in mid-February 2020. By this time, the selection of this regimen was based on its efficacy against the previous SARS-CoV-1 virus and its potential to inhibit viral replication of the SARS-CoV-2 in vitro. There was a shortage of robust clinical proof about the effectiveness of this regimen against the novel SARS-CoV-2. Therefore, extensive research effort has been made by several researchers worldwide to investigate whether this regimen is safe and effective for the management of COVID-19. In this review, we provided a comprehensive overview of the CQ/HCQ regimen, summarizing data from in vitro studies and clinical trials for the protection against or the treatment of SARS-CoV-2. Despite the initial promising results from the in vitro studies and the widespread use of CQ/HCQ in clinical settings during the 1st wave of COVID-19, current data from well-designed randomized controlled trials showed no evidence of benefit from CQ/HCQ supplementation for the treatment or prophylaxis against SARS-CoV-2 infection. Particularly, the two largest randomized controlled trials to date (RECOVERY and WHO SOLIDARITY trials), both confirmed that CQ/HCQ regimen does not provide any clinical benefit for COVID-19 patients. Therefore, we do not recommend the use of this regimen in COVID-19 patients outside the context of clinical trials

Global impact of COVID-19 on surgeons and team members (GlobalCOST): a cross-sectional study

Objectives To investigate the impact of COVID-19 on the well-being of surgeons and allied health professionals as well as the support provided by their institutions.Design This cross-sectional study involved distributing an online survey through medical organisations, social media platforms and collaborators.Setting It included all staff based in an operating theatre environment around the world.Participants 1590 complete responses were received from 54 countries between 15 July and 15 December 2020. The average age of participants was 30–40 years old, 64.9% were men and 32.5% of a white ethnic background. 79.5% were surgeons with the remainder being nurses, assistants, anaesthetists, operating department practitioners or classified other.Main outcome measures Participants that had experienced any physical illness, changes in mental health, salary or time with family since the start of the pandemic as well as support available based on published recommendations.Results 32.0% reported becoming physically ill. This was more likely in those with reduced access to personal protective equipment (OR 4.62; CI 2.82 to 7.56; p<0.001) and regular breaks (OR 1.56; CI 1.18 to 2.06; p=0.002). Those with a decrease in salary (29.0%) were more likely to have an increase in anxiety (OR 1.50; CI 1.19 to 1.89; p=0.001) and depression (OR 1.84; CI 1.40 to 2.43; p<0.001) and those who spent less time with family (35.2%) were more likely to have an increase in depression (OR 1.74; CI 1.34 to 2.26; p<0.001). Only 36.0% had easy access to occupational health, 44.0% to mental health services, 16.5% to 24/7 rest facilities and 14.2% to 24/7 food and drink facilities. Fewer measures were available in countries with a low Human Development Index.Conclusions This work has highlighted a need and strategies to improve conditions for the healthcare workforce, ultimately benefiting patient care

Global neurosurgery in the context of Global Public Health Practice - a literature review of case studies

Neurosurgical conditions are a substantial contributor to surgical burden in the world, with LMICs carrying a disproportionately large part. Policy initiatives such as the National Surgical, Obstetrics and Anesthesia Plans (NSOAPs) and CHYSPR have highlighted the need for an intersectoral approach, not just at the hospital level but on a large scale encompassing national public health strategies. This article aims to illustrate through case studies, how addressing this surgical burden is not limited to the clinical context but extends to public health strategies as well. For example, vitamin B12 and folic acid are micronutrients that, if not at adequate levels, can result in debilitating neurosurgical conditions. In Ethiopia, through coalesced efforts between neurosurgeons and policy makers, the government has made strides in implementing food fortification programs at a national level to address the neurosurgical burden. Traumatic brain injuries (TBIs) are another neurosurgical burden that unevenly affect LMICs. Countries such as Colombia and India have demonstrated the importance of legislation and enforcement, coupled with robust data collection and auditing systems and strong academic advocacy of neurosurgeons can drastically reduce TBIs. Despite the importance of public health efforts in addressing neurosurgical conditions, there is lack of neurosurgeon involvement in public health and lack of integration of neurosurgical burden in national health planning systems. It is imperative that neurosurgeons advocate for and are included in aspects of public health policy. Neurosurgery does not stop within the bounds of the hospital, and neither should the role of a neurosurgeon

Development and external validation of the 'Global Surgical-Site Infection' (GloSSI) predictive model in adult patients undergoing gastrointestinal surgery

Background: Identification of patients at high risk of surgical-site infections may allow surgeons to minimize associated morbidity. However, there are significant concerns regarding the methodological quality and transportability of models previously developed. The aim of this study was to develop a novel score to predict 30-day surgical-site infection risk after gastrointestinal surgery across a global context and externally validate against existing models. Methods: This was a secondary analysis of two prospective international cohort studies: GlobalSurg-1 (July-November 2014) and GlobalSurg-2 (January-July 2016). Consecutive adults undergoing gastrointestinal surgery were eligible. Model development was performed using GlobalSurg-2 data, with novel and previous scores externally validated using GlobalSurg-1 data. The primary outcome was 30-day surgical-site infections, with two predictive techniques explored: penalized regression (least absolute shrinkage and selection operator ('LASSO')) and machine learning (extreme gradient boosting ('XGBoost')). Final model selection was based on prognostic accuracy and clinical utility. Results: There were 14 019 patients (surgical-site infections = 12.3%) for derivation and 8464 patients (surgical-site infections = 11.4%) for external validation. The LASSO model was selected due to similar discrimination to extreme gradient boosting (AUC 0.738 (95% c.i. 0.725 to 0.750) versus 0.737 (95% c.i. 0.709 to 0.765)), but greater explainability. The final score included six variables: country income, ASA grade, diabetes, and operative contamination, approach, and duration. Model performance remained good on external validation (AUC 0.730 (95% c.i. 0.715 to 0.744); calibration intercept -0.098 and slope 1.008) and demonstrated superior performance to the external validation of all previous models. Conclusion: The 'Global Surgical-Site Infection' score allows accurate prediction of the risk of surgical-site infections with six simple variables that are routinely available at the time of surgery across global settings. This can inform the use of intraoperative and postoperative interventions to modify the risk of surgical-site infections and minimize associated harm